DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 04/30/2026 has been entered.
Claim Status
In the submission filed 04/30/2026, claim 14 has been cancelled. Claims 1 and 15 have been amended. Accordingly, claims 1-2, 4, 7-8, 15, 18 and 20 are pending and under current examination.
Priority
The instant application is a national stage entry of PCT application PCT/US2020/061578, filed 05/20/2022 under 35 USC 371. Acknowledgement is made of the applicant's claim for benefit to prior- filed U.S. provisional patent applications 62/938,094 (filed 11/20/2019).
Status of Prior Rejections/Response to Arguments
The objection to Drawing is withdrawn:
Applicant’s submission of replacement sheets is effective to obviate the objection on record. The objection is withdrawn.
The rejections to claims 1, 7, 8, 14, 15, 18 and 20 under 35 U.S.C. 103 over Bell et al., as evidenced by Hamza et al., in view of Guo et al., as evidenced by Luo et al. is maintained:
The rejections to claims 1, 2, 4, 7, 8, 14, 15, 18 and 20 under 35 U.S.C. 103 over Bell et al., as evidenced by Hamza et al., in view of Guo et al., as evidenced by Luo et al. , further in view of Wanger et al. is maintained:
The cancellation of claim 14 renders the rejection thereto moot.
Applicant’s amendment to claim 1 limits the second polypeptide comprises a polypeptide linker which is a flexible polypeptide linker. Applicant asserts that either combination of cited references teach or suggest such a recombinant vaccinia virus. Thus, the presently presented claims are patentable over the combination of cited references (Remarks, p2).
Applicant’s argument is fully considered but not found persuasive. Guo et al. teach the amended limitation. Specifically, Guo et al. teach p40 subunit, which is a common subunit of IL-12 and IL-23, can be linked to an anchoring peptide, optionally with a linker peptide between the p40 subunit and the anchoring peptide (p32, L4-5). Guo et al. also teach the linker peptide can be a cleavable linker, a non-cleavable linker, a peptide linker, a flexible linker, a rigid linker, a helical linker, a non-helical linker or a combination thereof (p27, L22-24). Based on Guo et al.’s teaching, it would have been prima facie obvious to one of ordinary skill in the art to modify Bell et al.’s orthopoxvirus vectors comprising IL-12 p70, which comprises a p40 subunit, a p35 subunit and a transmembrane domain (IL12-TMp70, or p40-p35-TM), and link the p40 subunit with a flexible polypeptide linker to the anchoring peptide as taught by Guo et al., with a predictable effect of anchoring the IL-12 to the membrane.
Applicant has further traversed the rejection, asserts that specification provides unexpected results, which disclosing how membrane bound IL-12 having a flexible linker provides unexpectedly superior results as compared to membrane bound IL-12 having a rigid linker (Remarks, p2). In response, the Examiner respectfully reminds Applicant that, in submitting evidence asserted to establish unobvious results, there is a burden on Applicant to indicate how the examples asserted to represent the claimed invention are considered to relate to the examples intended to represent the prior art and, particularly, to indicate how those latter examples do represent the closest prior art. MPEP § 2145. It should also be established that the differences in the results are in fact unexpected and unobvious and of both statistical and practical significance. MPEP § 716.02(b). In the instant case, Applicant has failed to indicate how the alleged unexpected results differ from the closest prior art, and has instead compared the membrane bound IL-12 having a flexible linker and the membrane bound IL-12 having a rigid linker within their own experimentation. The rejection is maintained in modified form to address amended limitations.
Modified Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 7, 8, 15, 18 and 20 stand rejected under 35 U.S.C. 103 as being unpatentable over Bell et al. (WO 2020/124274 A1, internation filing date 12/20/2019, designated to US, with a priority date of 12/21/2018, cited in IDS), as evidenced by Hamza et al. (Int. J. Mol. Sci. 2010, 11, 789-806), in view of Guo et al. (WO 2018/145033 Al, published 09/08/2018, cited in IDS), as evidenced by Luo et al. (J Mol Biol. 2010 Oct 8;402(5):797-812). The rejection is modified as necessitated by Applicant’s amendment.
Bell et al. teach modified orthopoxvirus vectors, as well as methods of using the same for the treatment of various cancers. The disclosure provides modified orthopoxvirus vectors that exhibit various beneficial therapeutic activities, including enhanced oncolytic activity, spread of infection, immune evasion, tumor persistence, capacity for incorporation of exogenous DNA sequences, amenability for large scale manufacturing, and safety (Abstract).
Regarding claim 1, Bell et al. teach genetically modified orthopoxviruses, such as vaccinia viruses that exhibit mutations in one or more, or all, of these genes may exhibit an array of beneficial features, such as improved oncolytic ability, replication in tumors, infectivity, immune evasion, tumor persistence, capacity for incorporation of exogenous DNA sequences, and/or amenability for large scale manufacturing. In various embodiments, the modified orthopoxvirus expresses at least one of three transgenes: Interleukin 12 containing a transmembrane domain (IL-12-TM), PMS-like tyrosine kinase 3 ligand (FLT3-L) and anticytotoxic T-lymphocyte Associated Protein 4 (CTLA-4) antibody (parag 0006). Bell et al. teach a second transgene comprising a second nucleotide sequence encoding an IL-12 polypeptide (parag 0031, also claim 11 in p686). In specific embodiments, the IL-12 polypeptide comprises IL-12 p35 or IL-12 p70 (parag 0018). In specific embodiments, the IL-12 polypeptide comprises IL-12 p70 (e.g., human IL-12 p70), which comprises a p40 subunit (e.g., human IL-12 p40) and a p35 subunit (e.g., human IL-12 p35), and a transmembrane domain (IL12-TMp70, or p40-p35-TM) (parag 00508). The transmembrane domain can be derived from any membrane-bound protein (e.g., B7-1, membrane-bound TNFa, or membrane-bound FLT3L). The cytoplasmic domain can be derived from any protein that contains a cytoplasmic domain (e.g., B7-1, TNFa, or FLT3L) (parag 00508). Since Bell et al. teach IL-12 p70 comprises two subunits (IL-12 p35 subunit and IL-12 p40 subunit), the teaching indicates the nucleotide sequence encoding an IL-12 polypeptide would comprises nucleic acids encoding an IL-12p35 polypeptide sequence, and nucleic acids encoding an IL-12 p40 polypeptide sequence, reads on “a recombinant vaccinia virus comprising a vaccinia virus genome comprising (a) nucleic acid encoding a first polypeptide and (b) nucleic acid encoding a second polypeptide, wherein said first polypeptide comprises an IL-12 p35 polypeptide sequence, wherein said second polypeptide comprises an IL-12 p40 polypeptide sequence” in instant claim. Bell et al. teach IL-12 polypeptide comprises IL-12 p70 comprising a transmembrane domain and cytoplasmic domain, e.g., p40-p35-TM, indicates that IL-12 p35 subunit connecting to a membrane anchoring polypeptide sequence. Bell et al. teach claims 11-12, a nucleic acid comprising a recombinant vaccinia virus genome comprising a second transgene comprising a second nucleotide sequence encoding an Interleukin 12 (IL-12) polypeptide, further comprising a nucleotide sequence comprising at least one promoter operably linked to the second nucleotide sequence (see p686). The teachings indicate that the promoter is able to regulate the expression of both p35 subunit and p40 subunit, which reads on “a promoter capable of driving transcription of a polycistronic transcript that expresses said first polypeptide and said second polypeptide” as recited in instant claim. Instant claim differs from Bell et al. at:
instant claim has the second polypeptide comprises an IL-12p40 polypeptide sequence, a flexible polypeptide linker, and a membrane anchoring polypeptide sequence (that is, the p40 subunit instead of p35 subunit links to a flexible polypeptide linker and a membrane anchoring polypeptide sequence);
there is an internal ribosome entry site (IRES) between said nucleic acid encoding said first polypeptide (IL-12p35) and said nucleic acid encoding said second polypeptide ((IL-12p40);
said membrane anchoring polypeptide sequence comprises a polypeptide capable of a glycosylphosphatidyl-inositol (GPI) modification.
However, such were disclosed by Guo et al. at the time of instant invention.
Guo et al. teach tumor infiltrated T cells induced by oncolytic virus ("OV-induced T cells"), methods of making and using said OV-induced T cells for an adoptive T-cell therapy. The disclosed subject matter further relates to oncolytic viruses and armed oncolytic viruses, methods of making and using said oncolytic viruses, as well as pharmaceutical compositions and kits comprising said oncolytic viruses (Abstract).
Regarding (1), Guo et al. teach an oncolytic vaccinia virus, comprising, in its genome, a nucleic acid, which is a deoxyribose nucleic acid, encoding IL-23p19 and IL-23p40. In certain embodiments,
the IL-23p19 and IL-23p40 are linked to an anchoring peptide, optionally with a linker peptide between IL-23p40 and the anchoring peptide (p32, L4-5). The linker peptide can be a cleavable linker, a non-cleavable linker, a peptide linker, a flexible linker, a rigid linker, a helical linker, a non-helical linker or a combination thereof (p27, L22-24). It is known and evidenced by Luo et al. that interleukin (IL)-12 and IL-23 are heterodimeric proinflammatory cytokines that share a common p40 subunit (Abstract). These teachings indicate that the p40 subunit is structurally available and capable of linking to a linker peptide and the anchoring peptide, wherein the linker peptide can be a flexible linker.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Bell et al.’s orthopoxvirus vectors comprises IL-12 p70 (e.g., human IL-12 p70), which comprises a p40 subunit (e.g., human IL-12 p40) and a p35 subunit (e.g., human IL-12 p35), and a transmembrane domain (IL12-TMp70, or p40-p35-TM), and use p40 subunit to link to the anchoring peptide with a linker (i.e., a flexible linker), as taught by Guo et al.. The only difference between instant claim and Bell et al.’s orthopoxvirus vectors comprising IL-12p70 (comprising IL-12 p35 subunit and IL-12 p40 subunit) and a transmembrane domain (IL12-TMp70, or p40-p35-TM) is instant claim comprises a p40 subunit linking to the transmembrane domain (membrane anchoring peptide) with a flexible polypeptide linker. Given that Guo et al. teach IL-23p40 are linked to an anchoring peptide, optionally with a linker peptide between IL-23p40 and the anchoring peptide (p32, L4-5), and the linker peptide can be a flexible polypeptide linker (p27, L23), as well as Luo et al. provide evidence that IL-12 and IL-23 share a common p40 subunit (Abstract), one of ordinary skill in the art would have substituted IL-12p35 polypeptide sequence and the membrane anchoring polypeptide sequence (e.g., p40-p35-TM), and link the p40 subunit with a flexible polypeptide linker to the transmembrane domain (membrane anchoring peptide), depends on the research interest and preferences. This simple substitution of one known element (IL-12 having p40 subunit link to a membrane anchoring peptide with a flexible polypeptide linker) for another known element (IL-12 having p35 subunit link to a membrane anchoring peptide) is likely to be obvious when predictable results are achieved. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, B.).
Regarding (2) , Guo et al. teach diagram of insertion, in vvDD thymidine kinase (tk) gene, of p7.5e/l viral promoter operably linked to murine IL-23p19-encoding nucleic acid fused to IRES linker and murine IL-23p40 anchor-encoding sequences, in virus denoted vvDD-mIL-23p19-IRES (p6, L8-11, figure 3).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Bell et al.’s orthopoxvirus vectors comprising IL-12p70 (comprising IL-12 p35 subunit and IL-12 p40 subunit) and a transmembrane domain, and uses IRES to separate the nucleic acid encoding the first polypeptide (IL-12p35) and the nucleic acid encoding the second polypeptide (IL-12p40) by IRES as taught by Guo et al.. The skilled artisan would have been motivated to use IRES between the first and second polypeptide since Guo et al. teach IRES can be used in the construct comprising IL-23p19 and IL-23p40 (two subunits of IL-23, see p23, L24-26) for successfully expressing IL-23. There would be a reasonable expectation of success of using IRES in the recombinant vaccinia virus, since the sequence of IRES is well known in the art, and a skilled artisan has the knowledge for placing IRES between two nucleic acid sequences encoding two polypeptides in a construct.
Regarding (3), Guo et al. teach in certain embodiments, the disclosed subject matter provides an oncolytic virus encoding a membrane-associated protein comprising an immunomodulator molecule linked to an anchoring peptide (p4, L10-13). In certain embodiments, the anchoring peptide comprises a GPI-anchor acceptor peptide or a PD-LI transmembrane domain (p4, L21-22). Guo et al. teach in certain embodiments, an anchoring peptide can be used according to the disclosed subject matter to modify an immunomodulator molecule to bind to the membrane of the host cell (e.g., by adding a GPI or other molecule).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Bell et al.’s orthopoxvirus vectors comprising IL-12p70 (comprising IL-12 p35 subunit and IL-12 p40 subunit) and a transmembrane domain, and use an anchoring peptide having a glycosylphosphatidyl-inositol (GPI) modification as taught by Guo et al.. The skilled artisan would have been motivated to use a GPI modification since Guo et al. teach using GPI modification can modify an immunomodulator molecule to bind to the membrane of the host cell (see p24, L30-33), which is beneficial for the treatment (of e.g., a tumor cell). There would be a reasonable expectation of success of having a glycosylphosphatidyl-inositol (GPI) modification for the anchoring polypeptide, since Guo et al. teach engineered vaccinia virus with a GPI anchoring peptide (see p52, Example 1) and exemplary sequences of GPI modification (e.g., see p26 and p52).
Regarding claim 7, Bell et al. do not teach said membrane anchoring polypeptide sequence is from about 10 amino acids to about 50 amino acids in length. However, Guo et al. teach in certain non-limiting embodiments, the anchoring peptide is between about 10 and about 50 amino acids, or between about 15 and about 30, or about 20 amino acids in length (p25, L1-3).
Regarding claim 8, Bell et al. do not teach said polypeptide capable of a GPI modification is derived from a CD16b polypeptide. However, Guo et al. teach in certain embodiments, the oncolytic virus can comprise a gene encoding a membrane-associated fusion protein that includes an immunomodulator molecule fused to an anchoring peptide, e.g., a GPI anchor (e.g., a GPI-anchor acceptor sequence of human CD16b)(p29, L13-16).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Bell et al.’s orthopoxvirus vectors comprising IL-12p70 (comprising IL-12 p35 subunit and IL-12 p40 subunit) and a transmembrane domain, and use an anchoring peptide capable of a glycosylphosphatidyl-inositol (GPI) modification (e.g., a GPI-anchor acceptor sequence of human CD16b) as taught by Guo et al.. The skilled artisan would have been motivated to use a GPI modification since Guo et al. teach using GPI modification can modify an immunomodulator molecule to bind to the membrane of the host cell (see p24, L30-33), which is beneficial for the treatment (of e.g., a tumor cell). There would be a reasonable expectation of success of having a glycosylphosphatidyl-inositol (GPI) modification for the anchoring polypeptide, since Guo et al. teach exemplary GPI anchoring peptide (e.g., a GPI-anchor acceptor sequence of human CD16b, see p29, L13-16).
Regarding claim 15, following the discussion above, Bell et al. do not teach said flexible polypeptide linker comprises a (G4S)3 sequence (SEQ ID NO:13). However, Guo et al. teach in certain embodiments, the peptide linker comprises a flexible linker. In certain embodiments, the flexible linker can be (G4S)3 (p28, L1-2).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Bell et al.’s orthopoxvirus vectors comprises IL-12 p70 (e.g., human IL-12 p70), which comprises a p40 subunit (e.g., human IL-12 p40) and a p35 subunit (e.g., human IL-12 p35), and a transmembrane domain (IL12-TMp70, or p40-p35-TM), and use p40 subunit to link to the anchoring peptide with a flexible linker, wherein the flexible linker is encoded by (G4S)3 sequence, as taught by Guo et al.. The only difference between instant claim and Bell et al.’s orthopoxvirus vectors comprising IL-12p70 (comprising IL-12 p35 subunit and IL-12 p40 subunit) and a transmembrane domain (IL12-TMp70, or p40-p35-TM) is instant claim comprises the p40 subunit linking to the transmembrane domain (membrane anchoring peptide) with a flexible polypeptide linker encoded by (G4S)3 sequence between the IL-12p40 polypeptide sequence and the membrane anchoring polypeptide sequence. Given that Guo et al. teach alternatively the immunomodulator molecule can be linked to the anchoring peptide via a linker (p27, L21-22), such as a flexible linker with a sequence of (G4S)3 (p28, L1-2), one of ordinary skill in the art would have substitute IL-12p35 polypeptide sequence and the membrane anchoring polypeptide sequence (e.g., p40-p35-TM), and use a flexible linker encoded by (G4S)3 sequence between IL-12p40 polypeptide sequence and the membrane anchoring polypeptide sequence, depends on the research interest and preferences. This simple substitution of one known element (using a flexible polypeptide linker such as a (G4S)3 sequence between IL-12p40 polypeptide sequence and the membrane anchoring polypeptide sequence) for another known element (IL-12p35 polypeptide sequence directly connect to the membrane anchoring polypeptide sequence) is likely to be obvious when predictable results are achieved. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, B.).
Regarding claim 18, Bell et al. teach using a late promoter such as an Fl 7R promoter, or a Dl3L promoter (see p686, claims 13-14) for the IL-12 polypeptide, do not teach the promoter is selected from the group consisting of a p7.5 e/l promoter and a pSe/l promoter. However, Guo et al. teach in certain embodiments, the nucleic acid encoding IL-2 is operably linked to a promoter active or activatable in an oncolytic virus-infected cell, for example, an oncolytic virus promoter (e.g., a vaccinia virus promoter)(p30, L9-12). Guo et al. teach in certain embodiment, said encoding nucleic acid can be operably linked to a vaccinia promoter, for example the p7.5 e/1 promoter, or the pSe/1 promoter to generate a promoter-encoding construct (p30, L25-27).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Bell et al.’s orthopoxvirus vectors comprising IL-12p70 (comprising IL-12 p35 subunit and IL-12 p40 subunit) and a transmembrane domain, and use a promoter such as a p7.5 e/l promoter and a pSe/l promoter which is capable of driving transcription of the first polypeptide and the second polypeptide, as taught by Guo et al.. The only difference between instant claim and Bell et al.’s orthopoxvirus vectors comprising IL-12p70 (comprising IL-12 p35 subunit and IL-12 p40 subunit) and a transmembrane domain is instant claim uses a promoter such as a p7.5 e/l promoter and a pSe/l promoter for the expression of IL-12 polypeptide. Given that Guo et al. teach using a vaccinia promoter such as the p7.5 e/1 promoter, or the pSe/1 promoter to generate a promoter-encoding construct (see p30, L25-27), one of ordinary skill in the art would have substituted Bell et al.’s late promoters such as an Fl 7R promoter or a Dl3L promoter, and use a vaccinia promoter such as the p7.5 e/1 promoter or the pSe/1 promoter for the expression of IL-12 polypeptide depends on their research interest or preference. This simple substitution of one known element (using a vaccinia promoter such as the p7.5 e/1 promoter or the pSe/1 promoter for the expression of IL-12 polypeptide) for another known element (using late promoters such as an Fl 7R promoter or a Dl3L promoter for the expression of IL-12 polypeptide) is likely to be obvious when predictable results are achieved. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, B.).
Regarding claim 20, Bell et al. teach in specific embodiments, the IL-12 polypeptide comprises IL-12 p70 (e.g., human IL-12 p70), which comprises a p40 subunit (e.g., human IL-12 p40) and a p35 subunit (e.g., human IL-12 p35), and a transmembrane domain (IL12-TMp70, or p40-p35-TM) (parag 00508). Bell et al. teach Examples 27, efficacy of SKV (vaccinia virus) expressing membrane bound IL-12p35-TM subunit versus IL12p70-TM subunit on tumor volume MC-38 mouse models (parag 00740). SKV-mIL12p35 and SKV-mIL12p70 treated mice showed comparable reductions in tumor volume (parag 00740). Bell et al. teach the function of IL12p70-TM, but do not specifically show the mechanism of IL12p70-TM. However, it is considered as an inherent property that IL-12p70 is a heterodimer of IL-12 p35 and IL-12 p40, and have the ability to stimulate an IL-12 receptor of another cell, which is evidenced by Hamza et al..
Hamza et al. provide evidence about the function and mechanism of IL-12p70. Hamza et al. teach that Interleukin 12 (termed IL-12p70 and commonly designated IL-12) is an important immunoregulatory cytokine that is produced mainly by antigen-presenting cells (Abstract), it is a heterodimeric cytokine (p790, parag 2). The biological activities of IL-12 are mediated via binding to a membrane receptor complex which is also composed of two subunits: IL-12R β1 and IL-12R β2 (p790, parag 5). This teaching reads on IL-12 p70 is in the form of a heterodimer having the ability to stimulate an IL-12 receptor of another cell, as recited in instant claim.
Claims 1, 2, 4, 7, 8, 15, 18 and 20 stand rejected under 35 U.S.C. 103 as being unpatentable over Bell et al. (WO 2020/124274 A1, internation filing date 12/20/2019, designated to US, with a priority date of 12/21/2018, cited in IDS), as evidenced by Hamza et al. (Int. J. Mol. Sci. 2010, 11, 789-806), in view of Guo et al. (WO 2018/145033 Al, published 09/08/2018, cited in IDS), as evidenced by Luo et al. (J Mol Biol. 2010 Oct 8;402(5):797-812), as applied to claims 1, 7, 8, 15, 18 and 20 above, further in view of Wagner et al. (US 2003/0105054A1, cited in IDS).
The teaching of Bell et al. and Guo et al. is set forth above.
Regarding claims 2 and 4, Bell et al. teach in specific embodiments, the IL-12 polypeptide comprises IL-12 p70 (e.g., human IL-12 p70), which comprises a p40 subunit (e.g., human IL-12 p40) and a p35 subunit (e.g., human IL-12 p35), and a transmembrane domain (parag 0507). Bell et al. do not specifically point out whether the p40 subunit or p35 subunit is a full length polypeptide. However, it is prima facie obvious in view of Wagner et al..
Wagner et al. teach immunogenic compositions for stimulating T cell proliferation and methods for enhancing therapeutic effectiveness of some traditional anti-cancer treatments. Specifically, local delivery of cytokines that target the plasma membrane of a cancerous cell exhibit more potent anti-tumor effects than systemic delivery of cytokines in soluble form (Abstract).
Regarding claims 2 and 4, Wagner et al. teach an immunogenic composition containing a vector comprising a nucleic acid encoding a factor that stimulates T cell proliferation attached to a sequence that signals a GPI anchor is described. It is preferred that the vector of the immunogenic composition is a plasmid or a virus vector. Preferably, the virus is a conditionally replicating adenovirus. Also preferred, the factor that stimulates T cell proliferation is a cytokine. Still preferred, the cytokine is IL-2 or IL-12 (parag 0011). In Example 1, Wagner et al. teach GPI anchored IL-12 expression vectors: the murine IL-12 B (p40) cDNA subunit was inserted into pcDNA3.1(+)/Zeo expression plasmid between EcoRI/XhoI sites. The stop codon was removed by PCR and the GPI anchor Sequence was inserted in frame into the same plasmid between XhoI and Xbal. Additionally, murine IL-12A (p35) cDNA was inserted into another pcDNA3.1(+)/Zeo plasmid between EcoRI/Xho sites with stop codon on it. The entire fragment of p35 and the pCMV promoter was cut off by BglII/StuI and blunt ended with Klenow. This fragment was inserted into pcDNA3.1(+)/Zeo-IL12-B-GPI plasmid which was cut with BglII and blunt ended with Klenow. The new recombinant plasmid was named pL12-A-BGPI and contains both the A and B subunit of IL-12, in which A is secreted and B is linked with a GPI anchor sequence (parag 0076). This GPI anchored IL-12 expression vector uses the cDNAs of IL-12 p40 and IL-12 p35 for expressing both the p35 and p40 subunit of IL-12, reads on “said IL-12p35 polypeptide sequence is a human IL-12p35 polypeptide sequence or a full length mouse IL-12p35 polypeptide sequence” in instant claim 2, and “ said IL-12p40 polypeptide sequence is a full length human IL-12p40 polypeptide sequence or a full length mouseIL-12p40 polypeptide sequence” in instant claim 4.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Bell et al.’s orthopoxvirus vectors comprising IL-12p70 (comprising IL-12 p35 subunit and IL-12 p40 subunit) and a transmembrane domain, and use a full length IL-12 p35 polypeptide sequence and a full length IL-12 p40 polypeptide sequence for encoding the IL-12 polypeptide comprises IL-12 p70, as taught by Wagner et al.. The skilled artisan would have been motivated to use the full length IL-12p35 polypeptide sequence (IL-12p35 cDNA) and IL-12p40 polypeptide sequence (IL-12p35 cDNA) for expressing IL-12, since Wagner et al. teach the IL-12 expression vector using IL-12 35p cDNA and IL-12 40p cDNA for successfully expressing functional IL-12 (see Examples). There would be a reasonable expectation of success of using a full length IL-12p35 polypeptide sequence and a full length IL-12p40 polypeptide sequence since Wagner et al. teach using the cDNAs of IL-12p35 and IL-12p40 for the IL-12 expression vector (Example 1), also the IL-12p35 cDNA and IL-12p40 cDNA was publicly accessible (e.g., GenBank).
Conclusion
No claims are allowed.
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/Q.G./Examiner, Art Unit 1633
/FEREYDOUN G SAJJADI/Supervisory Patent Examiner, Art Unit 1699
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